Alzheimer's disease (AD) is a progressive, neurodegenerative illness characterized by, but not limited to, the aggregation, and deposition of β-amyloid (Aβ) protein plaques in the neocortex, (e.g., J. Hardy and D. Selkoe, Science, 297, 353-356 (2002), and from abnormal activation of the glutamatergic N-methyl-D-aspartate receptors (NMDARs) [e.g., D. Choi, Neuron, 1(8), 623-634, (1988); and S. Lipton et al., New England Journal of Medicine, 330(9), 613-622 (1994)]. Plaques form when the normally occurring, trans-membrane amyloid precursor protein (APP) is broken down into peptide fragments and folded into dense deposits that impair neuronal functioning and eventually results in cellular death. The biochemical research has focused on finding drugs that would dissolve existing plaques or stop new ones from forming. Based on recent studies, formation and aggregation of soluble Aβ (1-42) oligomers are postulated to be a causative factor in the decline of cognitive function, and intervention of this biochemical pathway is a current therapeutic target [e.g., M. Necula et al., J. Biol. Chem., 282, 10311-10324 (2007); and F. De Felice et al., Neurobiol. Aging, in press (2007)].
Residing in the same areas of the brain affected by Aβ plaques are the N-methyl-D-aspartate receptors (NMDARs), which are part of an intricate signaling system involved in many physiological processes, including learning and memory. Upon NMDAR depolarization Ca2+ flows into the cell and modulates gene expression through a cascade of signaling mechanisms. Extended activation can cause morphological changes to postsynaptic dendritic spines and facilitate long-term potentiation (LTP), a momentary or long term enhanced synaptic signaling that occurs in learning and memory (e.g., J. Mothet et al., Aging Cell, 5(3), 267-274 (2006). Unmodulated activation of NMDAR (i.e. increased frequency of activation requiring lower concentration of glutamate) impairs the precision needed for neurotransmission, and leads to neurodegeneration. Within the glutamatergic synapse, plaque formation in combination with NMDAR dysfunction amplifies neuronal vulnerabilities [e.g., T. Harkany et al., Eur. J. of Neuroscience, 12(8), 2735-2745 (2000); M. Mattson et al., J. of Neuroscience, 12(2) 376-389 (1992); and H. Hsieh et al., Neuron, 52(5), 831-843 (2006)]. In cultured cortical neurons, Aβ decreased cell surface expression of the NMDAR and reduced NMDA-induced currents (e.g., E. Snyder et al., Nature Neuroscience, 8(8), 1051-1058 (2005). Consistent with these studies, Aβ aggregates impair cognition in AD transgenic mouse models [e.g., C. Haass and D. Selkoe, Nat. Rev. Mol. Cell. Biol., 8(2), 101-112, (2007); and S. Lesne et al., Nature, 440, 352-357, (2006)]. Despite evidence of dual pathology involving both Aβ aggregates and abnormal activation of NMDAR, treatment approaches have historically addressed these issues individually.
To date, the only FDA approved drug for the treatment of moderate to severe AD is memantine, (1-amino-3,5-dimethyladamantane), based on the results of a double blind, placebo controlled study [see B. Reisberg et al., N. Engl. J. Med. 348, 1333-1341 (2003)]. Memantine exerts neuroprotective effects in several models of brain injury in experimental animals [e.g., C. Parsons et al., Neuropharmacology 735-767 (1999); G. Wilcock, Lancet Neurol, 2, 503-505 (2003), G. Wenk et al., Behavioural Pharmacology, 17(5-6), 411-424, 2006)]. Memantine allows normal physiological NMDAR activity, while preventing pathological activation. Cognitive improvement in a transgenic mouse model of AD was noted three weeks after cessation of treatment, suggesting that in addition to providing symptomatic relief, memantine may have other disease-modifying properties as well [e.g., D. Dam et al., European Neuropsychopharmacology, 16(1), 59-69, (2006)].
O. Goel, WO/2007/117544, pub. Oct. 18, 2007, by the present inventor, describes novel carnitine conjugates of adamantanamines (e.g. memantine) and neramexane(s) as dual mechanism drugs for various therapeutic uses, including treating dementia of the Alzheimer's type. Memantine is also currently in clinical trials as an oral therapy for treating glaucoma. Amantadine (1-aminoadamantane) and rimantadine [1-(1-adamantyl)ethanamine], both as hydrochloride salts, are in clinical use as antiviral agents [e.g., P. Aldrich, et al., J. Med. Chem. 14, 535-543 (1972)]. Amantadine hydrochloride (Symmetrel®) is prescribed in the treatment of Parkinson's disease and drug induced extra pyramidal side effects. Amantadine and memantine are also suggested in the treatment of Huntington's disease [e.g., P. O'Suilleabhain et al., Arch. Neurol. 60(7), 996-8 (2003)]. A related substance, neramexane (1,3,3,5,5-pentamethylcyclohexylamine), has been in clinical studies for treating AD.
Alzheimer's research has recently begun to examine the role of copper in Aβ-associated aggregation and toxicity. Studies have shown that Cu2+ and Aβ peptides form complexes that induce Aβ aggregation and cause cognitive deficits [e.g., C. Atwood et al., J. of Biological Chem., 273(21), 12817-12826 (1998); J. of Neurochemistry, 75(3), 1219-1233 (2000); L. Sparks and B. Schreurs, PNAS, 100(19), 11065-11069 (2003); and A. Bush et al., Science, 265(5177), 1464-1467 (1994)]. In addition, in vitro and in vivo studies have reported that neurotoxicity seen in AD is, in part, the result of these complexes generating H2O2 [e.g., X. Huang et al., Biochemistry, 38(24), 7609-7616 (1999); J. of Biological Chem., 274(52), 37111-37116 (1999); and X. Zhu, et al., an update, Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 1772(4), 494-502 (2007)]. Postmortem studies have shown a significant increase in copper levels within neuritic plaques in subjects with AD, which is consistent with findings of oxidative damage in the brain (e.g., M. Lovell et al., J. of the Neurological Sciences, 158(1), 47-52 (1998), and the preceding X. Zhu update)]. Furthermore, higher serum copper levels in AD patients compared to cognitively normal individuals support a role for Cu2+ in AD pathophysiology [e.g., R. Squitti et al., Neurology, 59, 1153-1161 (2002); Neurology, 64(6), 1040-1046 (2005); Neurology, 67(1), 76-82 (2006); L. Rossi et al., J Nutr. Health Aging, 11(5), 408-417 (2007)].
Under normal physiological conditions, Cu2+ which modulates essential metabolic processes, including neurological function, is present in the brain at potentially toxic levels [e.g., A. Bush, Current Opinion in Chemical Biology, 4(2), 184-191 (2000)]. In the unbound ionic state Cu2+ causes oxidative damage, and protective mechanisms exist to regulate cellular levels via chaperone proteins, enzymes, storage proteins, organelles, and vesicles [e.g., E. Harris, Critical Reviews in Clinical Laboratory Sciences, 40(5), 547-586 (2003)].
Studies with the antibiotic clioquinol (iodochlorhydroxyquin), which chelates Cu2+ have been found to improve cognition in a subset of patients with AD, again suggesting that lowering copper levels has therapeutic benefits in the treatment of AD. The drug decreased deposition of Aβ and released soluble Aβ from preformed deposits both in vitro and in AD transgenic mice (e.g., C. Ritchie et al., Arch Neurol., 60, 1685-1691 (2003); and A. White et al., J. of Biological Chem. 281(26), 17670-17680 (2006)].
WO/2005/058293, published Jun. 30, 2005, claims use of memantine for treatment of proliferative retinal diseases such as proliferative diabetic retinopathy. Glutamate causes migration and proliferation of retinal pigment epithelium and/or glial cells. Glutamate antagonists, such as memantine can inhibit this pathology. A number of diseases of the eye such as age related macular degeneration caused by overgrowth of retinal blood vessels, which leak and damage vision, may be treated with anti-copper therapies (US Patent Appln. 20040259945, pub. Dec. 23, 2004).
Free copper is a known stimulant of angiogenesis critical to tumor growth and involved in rheumatoid arthritis [e.g., S. Brem, Cancer Control, 6, 5 (1999); A. Nasulewicz et al., Cell. Mol. Biol. Lett. 7, 308 (2002); US Patent Appln. 20040259945, pub. Dec. 23, 2004; and U.S. Pat. No. 7,189,865 (2007)].
G. Brewer in U.S. Pat. No. 6,855,340 (2005) discloses the benefits of copper complexing agents in the prevention and treatment of various inflammatory and fibrotic diseases such as pulmonary fibrosis, acute respiratory distress syndrome, liver cirrhosis and hepatitis C, kidney disease, cystic fibrosis, myocardial fibrosis, Alzheimer's disease, retinal inflammation, tissue transplant rejections, etc.
In the last two decades or more, various molecular compositions of inorganic thiomolybdates have emerged as relatively nontoxic copper-complexing therapeutics as alternatives to classical agents such as penicillamine and trientine. Ammonium tetrathiomolybdate (TM) is a potent Cu2+ complexing agent that has been used to bind excess circulating Cu2+ in patients with Wilson's disease and awaiting regulatory NDA filing (e.g., U.S. Pat. No. 6,855,340 (2005); and Arch Neurol., 63(4) 521-527). Recently, TM was shown to lower insoluble Aβ levels in transgenic mice (Tg2576) over expressing APP [see T. Wadsworth et al., abstract, Society for Neuroscience 37th Annual Meeting, San Diego (2007)].
The success of copper chelating agents, such as clioquinol, in treating and preventing Aβ aggregates, along with evidence of increased levels of circulating copper in AD patients, suggest thiomolybdic acid as a complementary pharmacophore to neuroprotective memantine for treating and arresting AD. While numerous complex polymetallic and hetrometallic (e.g. Fe—Mo) thiomolybdenum compounds are known, simple thiomolybdates are derived by stepwise sulfur exchange of oxygen in molybdic acid MO42− in alkaline media, resulting in intermediate mixed oxathio species which may be isolated with careful control of stochiometry. For practical reasons, it is easier to manufacture the perthiomolybdates, which simply precipitate from alkaline solutions as crystalline solids of well-defined compositions. The diammonium tetrathiomolybdate (TM) may be prepared in this manner. (It is commercially available from Aldrich Chemical Co. of Milwaukee, Wis., US.) However, TM is reportedly unstable under ambient conditions in air and humidity with ˜55% loss in activity after 50 days (US Patent Appln. 20040259945, pub. Dec. 23, 2004). To improve shelf life, the ammonium cations in amm.TM have been replaced with numerous hydrophobic polyalkyl (quaternary) ammonium cations potentially offering greater stability for pharmaceutical applications [e.g., US Patent Appln. 20040259945, pub. Dec. 23, 2004; and U.S. Pat. No. 7,189,865 (2007)]. However, these compounds in general, offer no additional pharmacological benefits or safety.
Tungsten, in the same group VIb elements, sits right under molybdenum in the periodic table, and has similar chemical properties. Thiotungstates may also be prepared from tungstic acid by oxygen to sulfur exchange. (Aldrich Chemical Co. of Milwaukee, Wis., US, markets ammonium tetrathiotungstate, and piperidine tetrathiotungstate.) R. Ternansky et al., disclose numerous polyalkylamino thiotungstates in US Patent Appln. 20060160805, pub. Jul. 20, 2006. In contrast to thiomolybdates, the thiotungstates are, however, malodorous and do not lend themselves easily to pharmaceutical applications. No clinical studies with thiotungstates have been found to be reported.
Clearly, a novel treatment that could act in concert with, and/or enhance the effects of memantine or related amines and also addresses plaque formation is of considerable clinical relevance.